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Enabling Technology : Biomaterials Evolution Platform

Enabling Technology : Biomaterials Evolution Platform. 9:05-9:35 4-Feb-2009 Wyss Institute for Biologically Inspired Engineering. Thanks to:. Feb 10. 8:30-9:00: Jim Collins - Anticipatory Medical Devices 9:05-9:35: George Church - Biomaterial Evolution

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Enabling Technology : Biomaterials Evolution Platform

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  1. Enabling Technology : Biomaterials Evolution Platform 9:05-9:35 4-Feb-2009 Wyss Institute for Biologically Inspired Engineering Thanks to:

  2. Feb 10 8:30-9:00: Jim Collins - Anticipatory Medical Devices 9:05-9:35: George Church - Biomaterial Evolution 9:40-10:10: Joanna Aizenberg - Adaptive Architectures 10:15-10:45: Don Ingber - Programmable Nanomaterials 10:50-11:20: Don Ingber Biomimetic Microsystems

  3. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  4. Sequencing tracked Moore’s law 2X/2 yr until 2005-9 10,000x/4yr $/bp 2005 $50M 2009 $5K 2009 goal of 2% for $200 (coding + regulatory)

  5. Open-architecture hardware, software, wetware e.g. 1981 IBM PC $150K - 2 billion beads/run Polonator Rich Terry Senior Engineer

  6. DNA Synthesis, assembly & analysis on chips Digital micromirror & inkjet Nitrobenzyl linkers for selective release of beads or cells

  7. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  8. Antibody (& TCR) VDJ regions VH*DH*NH*JH*Vkl*Jkl 46*23*N * 6 * 67* 5 = > 2M combinations , 750 bp, >1E10 cells Roth DB et al Mol Cell Biol. 1989 9:3049 N (1-13): 14 22 13 15 10 4 5 4 2 2 3 2 1 Lefranc, The Immunoglobulin FactsBook; Janeway, Immunobiology 2001

  9. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  10. First practical application of DNA nanostructures Residual NMR dipolar couplings for membrane proteins >15kDa Douglas, et al. PNAS 2007 10

  11. Selection of DNAs enabling selection of CNT structures Material properties change at the sub-nm scale (& sensitive to defects) Carbon Nanotubes Tensile strength: 62,000 MPa vs CNT-rope 3600, silk 1000, steel 800 Thermal conduction: 6000 W/mK vs Cu 385 Electrical current density of 4000 MA/cm2, vs Cu 4 C60 fullerite Bulk Modulus: 491 GPa vs diamond 442, steel 160 metalic vs. semiconducting

  12. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  13. Mirror world :resistant to enzymes, parasites, predators Approach#1: De novo Chemical synthesis (below) #2: Redesigned peptidyl transferase + D-AA-tRNAs (next slide) 352 AA Synthetic Dpo4 Sulfolobus DNA polymerase IV 4 peptide bonds left to construct D-aminoacids L-nucleotides (Mirror-biopolymers) L-aminoacids D-nucleotides (current biosphere) Duhee Bang

  14. Synthetic LifeHigh speed & accuracy Route to mirror proteinsJewett 113 kbp DNA 151 genes Pure translation: Forster & Church MSB ’05 GenomeRes.’06 Shimizu, Ueda ’01

  15. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  16. Genome Engineering Multiplex Automation (GEMA) for multi-viral resistance

  17. Genome Engineering Multiplex Automation (GEMASS)in vivo homologous allele replacement (lagging SS mimics) 3 hr Cycle time. Application: 314 change for multivirus resistance

  18. Improving process yield, health, safety: What threatens all biological systems? What do all viruses have in common? or lack?

  19. New genetic code: viral-resistance, novel amino acidsno functional GMO DNA exchange PEG-pAcPhe-hGH (Ambrx) high serum stability 314 TAG to TAA changes 4 Isaacs Charalel Church Sun Wang Carr Jacobson Kong Sterling 1 3 2

  20. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  21. Accelerated evolution for valuable metabolites & biofuels

  22. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

  23. Hair or skin sample Re-programming adult human cells to multiple tissues with combinations of DNAs

  24. Combinations of regulatory genes Viral delivery: β-catenin, Dnmt3l, Dppa2,3,4,5, Ecat1, Eras, Fthl17, Grb21, Ecat8, Fbx15, Gdf3, hTERT, Klf4, Myc, Nanog, Oct4, Rex1, Sall4, Sox2, Sox15, Stat3, Tcl1, Utf1 Signals:Activin, BMP4, Estrogen, FGF, HGF, PDGF, Retinoate, Shh, TGF, VEGF. Cartilage & bone Skin-derived stem cells Immature Brain Respiratory epithelium

  25. Biomaterials Evolution Platform • DNA Synthesis, assembly & analysis on chips • - VDJ-ome (antibody libraries) • 3-D DNA structures: inorganic interfaces • In vitro systems: multi-enzyme resistance • Microbial systems: multi-virus resistance • - Metabolic engineering fuels & chemicals • Human cell systems: combinatorial regulation • - Organ self-assembly

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